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Background/Objectives: This study aimed to evaluate layer-specific strain according to etiology and assess whether subtle changes in longitudinal and circumferential layer strain are involved in predicting cardiac mortality during a two-year follow-up in patients with dilated cardiomyopathy admitted with heart failure decompensation. Methods: 97 patients with dilated cardiomyopathy and a left ventricle ejection fraction ≤ 40% were recruited, 51 with ischemic and 46 with nonischemic etiologies. Conventional and two-dimensional speckle-tracking echocardiography (2D-STE) were conducted in dilated cardiomyopathy patients with a compensated phase of heart failure before discharge. Layer-specific longitudinal and circumferential strain was assessed from the endocardium, mid-myocardium, and epicardium by two-dimensional (2D) speckle-tracking echocardiography. The gradient between the endocardium and epicardium was calculated. Results: Patients with nonischemic etiology of dilated cardiomyopathy presented smaller values of global and layer strain than patients in the ischemic group. GLS, GLSend, GLSend-GLSepi, CSPMend, CSPMend-CSPMepi, CSAP, CSAPend, and CSAPend-CSAPepi were the parameters with statistically significant decreased values in non-survivors compared with survivors. In multivariate analysis, only CSPMend showed an independent value in predicting mortality at two-year follow-up. Receiver operator curve analysis provided CSPMend of −10.8% as a cut-off value with a sensitivity of 80% and specificity of 61.05% in identifying the dilated cardiomyopathy and heart failure patients with a risk of death at two-year follow-up. Conclusions: GLS, GCS, and layer-specific strain analysis showed decreased values in nonischemic compared with ischemic dilated cardiomyopathy and also in non-survivors compared with survivors. CSPMend was the most sensitive strain parameter to identify patients with increased mortality risk at two-year follow-up.